Chronic Granulomatous Disease (CGD) is an inborn error of immunity that can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) or experimental gene therapy. For viral vector-based in vivo gene therapy, the presence of preexisting antibodies to virus-llike particles (VLP) may have an impact on transduction. The prevalence of antibodies against VLPs that are derived from a chimeric Helper-Dependent Adenovirus (HDAd) is previously unknown.
A single blood draw was obtained in an observational clinical trial (NCT06605378) of patients in the United States and the United Kingdom confirmed to have CGD but had not previously undergone allo-HSCT or gene therapy. Total antibodies (TAb) were measured by an antibody bridging assay (capped to a titer of 2,048), and neutralizing antibodies (NAb) were measured by a transduction inhibition cell-based assay (capped to a titer of 1,024).
As of October 2025, 36 participants (median age 26, range 1–54 years; 33% under 18 years of age; 83% male, 11% Hispanic or Latino, 8% Asian, and 6% Black) with CGD (75% with mutations in CYBB) had a median TAb titer of 1,024 (≤32 [n = 6], 128 [n = 4], 512 [n = 3], 1,024 [n = 8], and 2,048 [n = 15]) and median NAb titer of 128 (≤32 [n = 5], 64 [n = 10], 128 [7], 256 [3], 512 [4], and 1,024 [n = 7]). For pediatric participants (<18 years of age), 67% were at or below the median TAb titer, and 75% were at or below the median NAb titer. For adults (≥18 years of age), 54% were at or below the median TAb titer, and 54% were at or below the median NAb titer. Both TAb and NAb were above the median 33% of the time, and both were at or below the median 53% of the time (86% overall agreement). Small numbers prevented formal comparisons.
Patients with CGD have varying preexisting exposure to VLP that may increase with age. The concordance between TAb and NAb in CGD participants was high. Understanding these results may help to better inform gene therapy for CGD patients.
